Knowledge concerning the pharmacology, biochemical organization and regulation of central dopaminergic neurons is crucial for obtaining a better understanding of the role played by these systems in normal and abnormal behavior. Gamma-hydroxybutyrate (GHB), an endogenous metabolite found in rodent, monkey and human brain when administered systemically produces a reversible lesion of the dopamine (DA) neurons in the nigro-neostriatal and mesolimbic DA pathways in rodent brain. Thus, normal mammalian brain contains and is capable of forming an endogenous compound which when administered systemically produces behavioral changes and an interruption of impulse flow in DA neurons. It is our aim to try to determine the functional role of this compound in the CNS and specifically to determine if this substance can modulate DA systems. We plan to study the metabolic routes for synthesis and degradation of GHB in primate and rodent brain and the enzymatic reactions involved and attempt to alter these processes pharmacologically; to investigate the mechanism by which GHB ultimately causes a suppression of impulse flow in the nigro-neostriatal pathway and to examine the structural requirements for this effect; to investigate endogenous levels and regional distribution in postmortem brains obtained from patients with neurological and psychiatric disorders; to determine the mechanism responsible for the activation of tyrosine hydroxylase resulting from an abolition of impulse flow in the nigro-striatal DA neurons and to determine if all DA neurons respond in a similar fashion; to investigate the effects of GHB and active analogs administered chronically and other DA drugs administered acutely and chronically on DA function with primary emphasis on the effects elicited by chronic treatment with antipsychotic drugs (APS); the studies with APS will be conducted both in rodents and Vervet monkeys; to examine the factors regulating tyrosine hydroxylase and in particular to attempt to determine the mechanisms invodved in the depolarization induced activation of tyrosine hydroxylase; to further investigate the role of presynaptic receptors in the modulation of DA synthesis; and finally attempt to learn more about the biochemical organization, regulatory control and potential sites for drug interaction with monoaminergic neurons in the CNS.